Synopsis: Maple syrup urine disease (MSUD) is a form of metabolic disorder that is passed down through families.

Quote:"There are a number of types of Maple Syrup Urine Disease (MSUD). The more common, or classic, form of the disorder usually produces symptoms in newborn infants between the ages of four and seven days."

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Defining MSUD

Maple syrup urine disease (MSUD) is a form of metabolic disorder that is passed down through families. The disorder affects people in a way that their bodies are unable to break down particular portions of proteins. The urine of people affected by this disorder may have the scent of maple syrup, thus the name of the disorder.

The year 1954 found Menkes describing a family in which four infants died within the first three months of their lives due to a neurodegenerative disorder. The infants urine presented an odor reminiscent of maple syrup, leading to the naming of the disorder as, 'Maple Sugar Urine Disease.' In the years that followed, Dancis was able to identify the pathogenetic compounds as branched-chain amino acids and corresponding alpha-keto acids. The year 1960 found Dancis demonstrating that the enzymatic defect in MSUD was at the level of the decarboxylation of the branched-chain amino acids. The first successful dietary treatment of MSUD was found by Snyderman, who restricted the intake of branched-chain amino acids. By the year 1971, Scriver reported the first person with thiamine-responsive MSUD. The year 1978 found the branched-chain alpha-keto acid, 'dehydrogenase (BCKD),' complex was purified and characterized.

Approximately one newborn out of one-hundred and eighty-thousand in America has MSUD, although it might be as common as one newborn in every one-hundred and seventy-six in selected populations such as the Mennonites in Pennsylvania. The fact that MSUD is an autosomal recessive disorder means that it is more prevalent in populations with a higher frequency of consanguinity. Around one newborn in a quarter-million in Austria has MSUD, as reported by the Austrian Screening Program.

Causes of MSUD

MSUD is caused by a deficiency of the BCKD complex. The BCKD complex catalyzes the decarboxylation of the alpha-keto acids of isoleucine, valine, and leucine to their respective branched-chain acyl-CoA's. These are further metabolized to produce acetyl-CoA, succinyl-CoA, and acetoacetate. The BCKD complex is associated with the inner mitochondrial membrane; it has three different catalytic components - E1, E2, and E3. BCKD also has two associated regulatory enzymes, BCKD kinase and BCKD phosphatase. The E1 component consists of two subunits, E1 alpha and beta, which form and alpha-2 heterotetramer. The E3 component is associated with two additional alpha-ketoacid dehydrogenase complexes, alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase. Mutations in E1, E2, or E3 cause MSUD. There are no good genotype-phenotype correlation between molecular and clinical phenotypes known, with the exemption of mutations in E2, which cause thiamine-responsive MSUD. Mutations in E3 cause deficiencies of alpha-ketoglutarate dyhydrogenases and pyruvate. There have been no reports of mutations in the regulatory enzymes.

The notable accumulation of leucine causes people affected by MSUD to experience neurological symptoms. Elevation of plasma isoleucine has been associated with the maple syrup odor of the urine of people with the disorder. Leucine is quickly transported across the blood-brain barrier of people with MSUD, where it is metabolized and yields glutamine and glutamate.

Symptoms of MSUD

There are a number of types of Maple Syrup Urine Disease (MSUD). The more common, or classic, form of the disorder usually produces symptoms in newborn infants between the ages of four and seven days. The symptoms of MSUD can include the following:

Coma

Seizures

Vomiting

Poor feeding

Poor weight gain

Increasing lethargy

Neurological damage

Difficulties with waking the infant up

Characteristic burned sugar smell to urine

Changes in muscle tone, muscle spasms, and seizures

Infants with MSUD who remain untreated will die within the first few months of their lives. People with intermittent MSUD, which is the second most common form of the disorder, will experience average development. When people with intermittent MSUD become ill; however, they display the classic signs of MSUD. Intermittent MSUD is a more rare form of the disorder. People with this form of MSUD have three to thirty-percent of the average level of BCKD enzyme, meaning the symptoms of MSUD might start at any age. People who experience thiamine-responsive MSUD, another form of the disorder, have shown improvement when taking thiamine supplements. There is an extremely rare form of MSUD referred to as, 'E3-deficient MSUD.' People with this form of the disorder have additional deficient metabolic enzymes.

Diagnosing MSUD

Should a doctor suspect that a person has MSUD, based upon the presentation of physical symptoms in the person - particularly the presence of that characteristic maple syrup odor associated with the person's urine, the doctor may order a blood test for amino acids. If alloisoleucine is detected in the person's blood, a diagnosis of MSUD is confirmed. There are a number of states in America that screen newborns at the time of their birth for MSUD. Additional testing that may be performed include the urine amino acid test and plasma amino acid test. People with MSUD will present with signs of ketosis and excess acid in their blood, also referred to as, 'acidosis.'

Treatment of MSUD

Once a person has been diagnosed with MSUD, and during episodes, treatment of the disorder involves the consumption of foods that are free of proteins. Sugars, fluids, and potentially fats, are administered intravenously. Hemodialysis or peritoneal dialysis may be used in order to reduce the level of amino acids in the affected person. Once the person's amino acid levels have reach average levels, they are placed on a diet that is free of branched-chain amino acids. A health care provider follows the person's amino acid levels closely, adjusting the person's diet according to the person's amino acid levels.

The long-term treatment of MSUD requires a unique diet that includes artificial infant formula containing low-levels of amino acids such as isoleucine, leucine, and valine. People with MSUD have to remain on a diet that is low in amino acids on a permanent basis. The importance of following a diet that is low in amino acids cannot be over-emphasized for persons with MSUD. The diet is essential for the prevention of nervous system damage. Blood testing to assess the levels of amino acids in the person's blood stream is something that must be pursued frequently, and closely supervised by a registered dietitian and a physician. Cooperation on the part of the person's family members is equally crucial.

MSUD may be life-threatening if it goes untreated. Even if people with the disorder pursue dietary treatment, situations that are stressful, or illness, may still cause high levels of certain amino acids in them. Episodes caused by stress or illness may lead to the death of the individual. By following strict dietary treatment, children with MSUD have grown into healthy adulthood.

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